This invention concerns novel norbornyl derivatives of thio- and dithio-carbanilic acid and their use as immunoregulatory agents.
Some of the compounds also have shown activity as hypotensive agents.
2. The Prior Art
Certain derivatives of thio and dithiocarbanilic acids are known in the prior art.
See, for example, Garraway, J. L., J. Chem. Soc. 1961: 3733 which describes the .omega.-carboxyalkyl dithiocarbanilates as precursors for the corresponding cyclic lactams (i.e., rhodanines an thiazine analogs). Further with respect to the production of rhodanine or thiazine analogs for corresponding .omega.-carboxyalkyl dithiocarbanilate precursors, see U.S. Pat. No. 3,781,434; Brown, F. C., et al., J.A.C.S., 78: 384 (1956); and Werbel, L. M., et al., J. Med. Chem. 11(2):364 (1968). The former reference describes the antiarthritic use of the cyclic thiazines, while the latter references describe the cyclic rhodanine derivations as antifungicidal, antibacterial, and antimalarial agents.
.omega.-Carboxymethyl 2,3-dihalo-dithiocarbanilates are described in British Published Secification No. 1,153,487 as anthelmintics. Further, U.S. Pat. No. 3,089,877 describes .omega.-(amidocarbonyl)alkyl dithiocarbonylates as fungicidal agents. Finally, U.S. Pat. No. 3,686,413 describes the anthelmintic use of dithiocarbanilates, including, inter alia, compounds of the formula ##STR1## wherein R.sub.3 is hydrogen or alkyl of 1 to 4 carbon atoms, inclusive; wherein p is the integer 1 or 2;
wherein X is chloro, bromo, or nitro; and PA1 wherein q is the integer 0 to 5, inclusive.
Thiocarbanilates, dithiocarbanilates, bisthiocarbanilates and bisdithiocarbanilates are disclosed as plant treating agents in British Pat. No. 811,861. These compounds have the formula ##STR2## wherein Q.sub.1, Q.sub.2 and Q.sub.3 may be hydrogen, alkyl or aralkyl groups, X.sub.1 designates a bivalent hydrocarbon group or a bivalent aliphatic chain containing more than 3 carbon atoms and divided by at least one nitrogen atom into alkylene groups consisting each of at least two carbon atoms, X.sub.2 and X.sub.3 designate hydrogen, or bivalent hydrocarbon atoms, i.e., when X.sub.2 and X.sub.3 form a heterocyclic ring with the bond N--X--N. M designates a salt forming group or a metal atom. B.sub.1 and B.sub.2 designate hydrogen atoms and/or alkyl-groups or constitute with the nitrogen atoms, a ring of 6 atoms at the most, B.sub.3 designates a bivalent, if desired substituted, alkylene, aralkylene or arylene group. B.sub.5 designates a bivalent alkylene, aralkylene or arylene group, for example, a phenylene group, or together with two nitrogen atoms and the two groups R.sub.2 forms a ring of not more than 6 atoms, or together with one nitrogen atom and the group R.sub.2 attached to this atom, a ring of not more than 6 atoms, X designates an NH.sub.2, a substituted NH.sub.2 --group, an OH--group in which the hydrogen atom is replaced by a cation, an alkyl, aralkyl- or aryl-group and finally Z designates an oxygen atom or a sulphur atom.
In addition to the uses of the dithiocarbanilates described above, certain chemical and biological investigations relating to such compounds have been undertaken and are reported in papers deposited in The California Polytechnic State University Library in San Luis Obispo, California. These papers are identified by author and title, as follows: Bello, J., "Some Effects of Newly Synthesized Thiocarbamates on Blood and Organ Parameters in the Mouse and Pig", Booth, J. "The Effects of 3-(N-Meta Fluorophenyl Dithiocarbamoyl) Propanic Acid on BAPN Induced Lathyrism in the Rat"; Burdick, P. R., "Warfarin Activity Modification and Other Effects of Some New Thiocarbamates in Mice"; Foster, R., "Modification of the Erythrocyte Membrane in Swine"; Jones, P., "Histological Effects of Carbamate Derivatives on the Spleen and Thymus of Swiss-Webster Mice"; Lash, L. D., "Leukocyte Depression and Other Responses in the Mouse, Produced by Datisca and a Novel Thiocarbamate"; Meyer, O., "The Effects of 3(N-Metafluorophenyl)Dithiocarbamoyl Propanoic Acid on the Lathrytic Condition Induced by Beta-Aminopropionitrile", Mortensen, M. L., "The Synthesis of Some of the Reaction Products of Isocyanates and Isothiocyanates with 3-Mercaptopropionic Acid"; and Reid, A., "Modification of Lathyrism in Rats by Three New Thiocarbamates".
Belgian Pat. No. 862,725 (Derwent Accession No. 33497/19) discloses penicillamine compounds and their acid addition salts that have immunosuppressive and antiinflammatory activity. The compounds have the formula ##STR3## (where R' is H, alkyl, alkenyl, alkoxycarbonyl, aryl, diphenylmethyl, heteroaryl, or the group ##STR4## R.sup.4 and R.sup.5 singly are alkyl aryl or aralkyl, or R.sup.4 and R.sup.5 together with the attached N or O atom, R.sup.2 is alkyl, aryl, aralkenyl, aryloxyalkyl, or heteroaryl, optionally subtituted by alkyl, R.sup.3 is H or alkyl, A is 1-5C alkylene, B is alkyl, R.sup.3 is H or alkyl, A is 1-5C alkylene, B is --CO-- or --CO.sub.2 --). In each case, the aryl, aralkyl, aralkenyl or heteroaryl groups are optionally substituted by .ltoreq.1 alkyl, alkoxy, halo, NO.sub.2, CF.sub.3, methylenedioxy, alkylsulphonamido, arylsulphonamido, trifluoromethylsulphonamido, acyl or acetoxy groups.
Immunoregulatory agents may be either immunosuppressive or immunostimulatory. For the purposes of the present invention immunoregulation shall make reference to the process of immunosuppression in response to a disease or other condition results from hyperimmunity in the animal or patient. Immunosuppressive use of .omega.-carboxyalkyl, the use of immunosuppressive agents in the treatment of and .omega.-(alkoxycarbonyl)alkyl esters of dithiocarbanilic acid and certain aryl-substituted acids related thereto are found in U.S. Pat. No. 4,110,440 and copending Ser. No. 848,433. For a comprehensive review of the use of immunosuppressive agents in the hyperimmunity diseases, see Camiener, G. W. et al., Progress in Drug Research 16:67 (1972) and Wechter, W. J., et al., Progress in Drug Research 20:573 (1976).
Many known immunosuppressive agents are cytotoxic and are believed in part to accomplish the immunosuppressive effects via a cytotoxic mechanism on the immunoactive organs (e.g., bone marrow and thymus). For example, the known antineoplastic agents, cyclohosphamide has been used in the treatment of arthritis. See Skinner, M. D., et al., Rheumatology 5:1 (1974).
Finally, anthelmintics such as niridazole have been employed immunosuppressively to control allograft rejection; while an other anthelmintic, levamisole, is apparently a non-specific stimulator of the immune system. See Daniels, J. D. et al., J. Immuno, 115-1414 (1975) and Renorex, G., et al., J. Immun. 109:761 (1972).